Gamma interferon is an essential cytokine for mediation of immune functions that are critical for surveillance against infections and cancer. Important aspects of innate immunity, adaptive immunity, macrophage activation, natural killer cell activity, helper T cell responses, as well as cytotoxic T cell responses are all critically modulated by IFN gamma. We have developed small peptide mimetics of IFN gamma. The IFN gamma mimetics exhibit antiviral activity against a variety of viruses including amelioration of the lethal effects of the poxvirus vaccinia in mice under conditions where intact IFN gamma is ineffective because of anti-IFN proteins produced by poxviruses. The activating effects of IFN gamm are suppressed by proteins called suppressors of cytokine signaling (SOCS), of which SOCS-1 is an important member. We have developed small molecule mimetics of SOCS-1 as well as a small molecule SOCS-1 antagonist. In this renewal, we propose to study the interaction between IFN gamma, IFN gamma mimetics, SOCS-1 mimetics, and SOCS-1 antagonists as per AIMs below to positively and negatively regulate the IFN responses of cells of the immune system and enhancement of protection of mice against vaccinia and ectromelia viruses with a view toward an IFN drug against smallpox. We hypothesize that our small peptide IFN mimetics represent novel antivirals against lethal poxvirus infections. 1. Protection of mice against lethal vaccinia virus infections by IFN mimetics. Effect of SOCS-1 mimetics and their antagonists on protection. 2. Compare intraperitoneal versus oral administration of IFN mimetic peptides for their relative ability to protect mice against lethal vaccinia virus infection. Effect of SOCS-1 antagonist. 3. Protection of mice against lethal ectromelia virus infection by IFN mimetics and SOCS-1 antagonists. 4. Determine immunological aspects of treatment of mice with IFN mimetics. Effect of SOCS-1 antagonist.